The T cell receptor (TCR), a heterodimer comprised of α and β chains derived by recombination in the thymus, enables T cells to recognize non-self ligands presented in the context of conventional and non-conventional major histocompatibility (MHC) molecules. Conventional MHC molecules have undergone divergent evolution to present a broad array of peptides However, the non-conventional CD1 molecules are highly conserved and present lipid and glycolipid antigens (Van Rhijn I et al, Nat Rev Immunol 15, 643-654 (2015); incorporated by reference herein). Like CD1, MR1 is a non-conventional MHC molecule that is highly conserved and located on human chromosome 1 (Riegert P et al, J Immunol 161, 4066-4077 (1998); incorporated by reference herein). CD1 presents small molecules from microbes such as Mycobacterium tuberculosis, Salmonella typhimurium, and Candida albicans (Gold M C et al, PLoS Biol 8 e1000407 (2010); Gold M C et al, J Exp Med 211, 1601-1610 (2014); Le Bourhis L et al, Nat Immunol 11, 701-708 (2010); all of which are incorporated by reference herein). MR1-restricted T cells (MR1Ts) are the T cell subset that recognizes these microbial small molecules bound to MR1 (Gold 2010 supra, Le Bourhis 2010 supra, Dusseaux M et al, Blood 117, 1250-1259 (2011); Kjer-Nielsen L et al, Nature 491, 717-723 (2012); Treiner E et al, Nature 422, 164-169 (2003); all of which are incorporated by reference herein). Mucosal-associated invariant T cells (MAITs), a subset of human MR1Ts, were defined by the use of a semi-invariant T cell receptor that includes a single c chain rearrangement (TRAV1-2 and TRAJ33) paired with a limited number of 3 chains (TRBV6 and TRBV20) (Treiner 2003 supra). The use of a highly conserved antigen presentation molecule along with limited TCR diversity suggested that MAIT cells were limited to recognizing a small repertoire of ligands and unable to discriminate between ligands (Huang S et al, Proc Natl Acad Sci USA 106, 8290-8295 (2009); incorporated by reference herein).
That the known activating ligands for MAIT cells are solely derived from the riboflavin biosynthesis pathway, (Kjer-Nielsen 2012 supra, Corbett A J et al, Nature 509, 361-365 (2014); incorporated by reference herein), and that only microbes that synthesize riboflavin were initially demonstrated to stimulate MAIT cells was viewed as further proof of this restriction. Furthermore, the semi-invariant nature of the MAIT cell TCR has been used to argue that MAIT cells do not possess properties of immunologic memory, specifically antigen-driven clonal expansions reflective of antigenic exposure and persistence. However, recent evidence of diverse TCR usage among MR1T cells (Gold 2014 supra; Gherardin N A et al, Immunity 44, 32-45 (2016); Meermeier E W et al, Nat Commun 16, 12506 (2016); both of which are incorporated by reference herein) and structural flexibility in the MR1 binding pocket (Lopez-Sagaseta et al, J Immunol 191, 5268-5277 (2013); incorporated by reference herein) raise the possibility of ligand diversity and the ability to discriminate between specific microbes.